RESUMO
Hypoxia and overexpression of glutathione (GSH) are typical characteristics of the tumor microenvironment, which severely hinders cancer treatments. Here, we design a novel biodegradable therapeutic system, O2-Cu/ZIF-8@Ce6/ZIF-8@F127 (OCZCF), to simultaneously achieve GSH depletion and O2-enhanced combination therapy. Notably, the doped Cu2+ doubles the O2 storage capacity of the ZIF-8 matrix, which makes OCZCF an excellent pH-sensitive O2 reservoir for conquering tumor hypoxia, enhancing the photodynamic therapy (PDT) efficiency of chlorin e6 (Ce6) under 650 nm laser irradiation. Moreover, the released Cu2+ can act as a smart reactive oxygen species protector by consuming intracellular GSH. The byproduct Cu+ will undergo highly efficient Fenton-like reaction to achieve chemodynamic therapy (CDT) in the presence of abundant H2O2. The accompanying O2 will further alleviate hypoxia. The in vitro and in vivo experimental data indicate that OCZCF could cause remarkable tumor inhibition through enhanced synergetic PDT and CDT, which may open up a new path for cancer therapy.
Assuntos
Nanocompostos , Neoplasias Experimentais , Fotoquimioterapia , Polietilenos , Polipropilenos , Porfirinas , Microambiente Tumoral/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Clorofilídeos , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Nanocompostos/química , Nanocompostos/uso terapêutico , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Polietilenos/química , Polietilenos/farmacocinética , Polietilenos/farmacologia , Polipropilenos/química , Polipropilenos/farmacocinética , Polipropilenos/farmacologia , Porfirinas/química , Porfirinas/farmacocinética , Porfirinas/farmacologiaRESUMO
Poly(propylene imine) dendrimers have been shown to be promising 3-dimensional polymers for the use in the pharmaceutical and biomedical applications. Our aims of this study were first, to synthesize a novel type of dendrimer with poly(propylene imine) core and maltose-histidine shell (G4HisMal) assessing if maltose-histidine shell can improve the biocompatibility and the ability to cross the blood-brain barrier, and second, to investigate the potential of G4HisMal to protect Alzheimer disease transgenic mice from memory impairment. Our data demonstrate that G4HisMal has significantly improved biocompatibility and ability to cross the blood-brain barrier in vivo. Therefore, we suggest that a maltose-histidine shell can be used to improve biocompatibility and ability to cross the blood-brain barrier of dendrimers. Moreover, G4HisMal demonstrated properties for synapse and memory protection when administered to Alzheimer disease transgenic mice. Therefore, G4HisMal can be considered as a promising drug candidate to prevent Alzheimer disease via synapse protection.
Assuntos
Histidina/uso terapêutico , Maltose/uso terapêutico , Transtornos da Memória/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , Polipropilenos/uso terapêutico , Doença de Alzheimer/complicações , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Animais , Linhagem Celular , Dendrímeros/química , Dendrímeros/farmacocinética , Dendrímeros/uso terapêutico , Histidina/análogos & derivados , Histidina/farmacocinética , Humanos , Maltose/análogos & derivados , Maltose/farmacocinética , Transtornos da Memória/complicações , Transtornos da Memória/patologia , Camundongos , Camundongos Transgênicos , Nanopartículas/química , Nanopartículas/uso terapêutico , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacocinética , Polipropilenos/química , Polipropilenos/farmacocinética , Sinapses/efeitos dos fármacos , Sinapses/patologiaRESUMO
Stimuli-responsive nanocarriers have attracted increased attention as materials that can facilitate drug and gene delivery in cancer therapy. The present study reports the development of redox-sensitive dendrimersomes comprising disulfide-linked cholesterol-bearing PEGylated dendrimers, which can be used as drug and gene delivery systems. Two disulfide-linked cholesterol-bearing PEGylated generation 3 diaminobutyric polypropylenimine dendrimers have been successfully synthesized via an in situ two-step reaction. They were able to spontaneously self-assemble into stable, cationic, nanosized vesicles (or dendrimersomes) with lower critical aggregation concentration values for high-cholesterol-bearing vesicles. These dendrimersomes were able to entrap both hydrophilic and hydrophobic dyes, and they also showed a redox-responsive sustained release of the entrapped guests in the presence of a glutathione concentration similar to that of a cytosolic reducing environment. The high-cholesterol-bearing dendrimersomes were found to have a higher melting enthalpy, increased adsorption tendency on mica surface, entrapping ability for a larger amount of hydrophobic drugs, and increased resistance to redox-responsive environments in comparison with their low-cholesterol counterpart. In addition, both dendrimersomes were able to condense more than 85% of the DNA at all the tested ratios for the low-cholesterol vesicles, and at dendrimer : DNA weight ratios of 1 : 1 and higher for the high-cholesterol vesicles. These vesicles resulted in an enhanced cellular uptake of DNA, by up to 15-fold when compared with naked DNA with low-cholesterol vesicles. As a result, they increased the gene transfection on the PC-3 prostate cancer cell line, with the highest transfection being obtained with low-cholesterol vesicle complexes at a dendrimer : DNA weight ratio of 5 : 1 and high-cholesterol vesicle complexes at a dendrimer : DNA weight ratio of 10 : 1. These transfection levels were about 5-fold higher than those observed when treated with naked DNA. These cholesterol-bearing PEGylated dendrimer-based vesicles are, therefore, promising as redox-sensitive drugs and gene delivery systems for potential applications in combination cancer therapies.
Assuntos
Colesterol , Dendrímeros , Sistemas de Liberação de Medicamentos/métodos , Técnicas de Transferência de Genes , Polietilenoglicóis , Polipropilenos , Neoplasias da Próstata , Linhagem Celular Tumoral , Colesterol/química , Colesterol/farmacocinética , Colesterol/farmacologia , Dendrímeros/química , Dendrímeros/farmacocinética , Dendrímeros/farmacologia , Humanos , Masculino , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/farmacologia , Polipropilenos/química , Polipropilenos/farmacocinética , Polipropilenos/farmacologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapiaRESUMO
Microcystin (MC) is a hepatotoxin produced by various cyanobacteria during harmful algal blooms (HAB's) in freshwater environments. Advanced treatment methods can remove MC from drinking water, but are costly and do not address recreational water exposure and ecosystem health concerns. Here we investigate the feasibility of utilizing plastics as a MC-adsorbing material, for use in water resources used for recreation, agriculture, aquaculture and drinking water. Water containing 20 µg/L MC-LR was exposed to polypropylene (PP) plastic for a six-day period at varying temperatures (22, 37, 65°C). Water samples were then collected at 0, 1, 2, and 6 hour-intervals to examine short term treatment feasibility. Samples were also taken at 24 hours, 3 days, and 6 days to determine long-term treatment effectiveness. MC concentrations were analyzed using ELISA. Results showed a maximal reduction of nearly 70% of MC-LR after a 6-day treatment with PP at 65°C. Temperature enhanced MC-LR reduction over a 6-day period: 70% reduction at 65°C; 50% at 37°C; 38% at 22°C. We propose an inexpensive intervention strategy which can be deployed rapidly on-site in various source waters, including in resource-limited settings. During the high peak of HAB season, the strategy can be applied in source waters, alleviating water treatment burden for treatment plants, lowering treatment costs and reducing chemical usage.
Assuntos
Microcistinas/isolamento & purificação , Plásticos/química , Polipropilenos/química , Purificação da Água/métodos , Adsorção , Análise Custo-Benefício , Cianobactérias/metabolismo , Ecossistema , Proliferação Nociva de Algas/fisiologia , Humanos , Toxinas Marinhas , Microcistinas/metabolismo , Plásticos/farmacocinética , Polipropilenos/farmacocinética , Reciclagem , Instalações de Eliminação de Resíduos/economia , Purificação da Água/economiaRESUMO
Topical nitric oxide (NO) delivery has been shown to accelerate wound healing. However, delivering NO to wounds at appropriate rates and doses requires new biomaterial-based strategies. Here, we describe the development of supramolecular interpolymer complex hydrogels comprising PEO-PPO-PEO (F127) micelles embedded in a poly(acrylic acid) (PAA) matrix, with S-nitrosoglutathione (GSNO) molecules dissolved in the hydrophilic domain. We show that PAA:F127/GSNO hydrogels start releasing NO upon hydration at rates controlled by their rates of water absorption. SAXS measurements indicate that the supramolecular structure of the hydrogels retains long-range order domains of F127 micelles. The PAA/F1227 hydrogels displayed dense morphologies and reduced rates of hydration. The NO release rates remain constant over the first 200â¯min, are directly correlated with the hydration rates of the PAA:F127/GSNO hydrogels, and can be modulated in the range of 40â¯nmol/gâ¯h to 1.5⯵mol/gâ¯h by changing the PAA:F127 mass ratio. Long-term NO-release profiles over 5â¯days are governed by the first-order exponential decay of GSNO, with half-lives in the range of 0.5-3.4â¯days. A preliminary in vivo study on full-thickness excisional wounds in mice showed that topical NO release from the PAA:F127/GSNO hydrogels is triggered by exudate absorption and leads to increased angiogenesis and collagen fiber organization, as well as TGF-ß, IGF-1, SDF-1, and IL-10 gene expressions in the cicatricial tissue. In summary, these results suggest that hydration-controlled NO release from topical PAA:F127/GSNO hydrogels is a potential strategy for enhancing wound healing. STATEMENT OF SIGNIFICANCE: The topical delivery of nitric oxide (NO) to wounds may provide significant beneficial results and represent a promising strategy to treat chronic wounds. However, wound dressings capable of releasing NO after application and allowing the modulation of NO release rates, demand new platforms. Here, we describe a novel strategy to overcome these challenges, based on the use of supramolecular poly(acrylic acid) (PAA):F127 hydrogels charged with the NO donor S-nitrosoglutathione (GSNO) from whereby the NO release can be triggered by exudate absorption and delivered to the wound at rates controlled by the PAA:F127 mass ratio. Preliminary in vivo results offer a proof of concept for this strategy by demonstrating increased angiogenesis; collagen fibers organization; and TGF-ß, IGF-1, SDF-1, and IL-10 gene expressions in the cicatricial tissue after topical treatment with a PAA:F127/GSNO hydrogel.
Assuntos
Resinas Acrílicas , Hidrogéis , Óxido Nítrico , Polietilenos , Polipropilenos , Cicatrização/efeitos dos fármacos , Ferimentos e Lesões , Resinas Acrílicas/farmacocinética , Resinas Acrílicas/farmacologia , Animais , Citocinas/biossíntese , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hidrogéis/química , Hidrogéis/farmacocinética , Hidrogéis/farmacologia , Camundongos , Micelas , Óxido Nítrico/química , Óxido Nítrico/farmacocinética , Óxido Nítrico/farmacologia , Polietilenos/química , Polietilenos/farmacocinética , Polietilenos/farmacologia , Polipropilenos/química , Polipropilenos/farmacocinética , Polipropilenos/farmacologia , S-Nitrosoglutationa/química , S-Nitrosoglutationa/farmacocinética , S-Nitrosoglutationa/farmacologia , Ferimentos e Lesões/tratamento farmacológico , Ferimentos e Lesões/metabolismo , Ferimentos e Lesões/patologiaRESUMO
Medical devices decorated with salicylic acid-based polymer chains (polymeric prodrug) that slowly release this anti-inflammatory and anti-biofilm drug at the implantation site were designed. A "grafting from" method was implemented to directly grow chains of a polymerizable derivative of salicylic acid (2-methacryloyloxy-benzoic acid, 2MBA) onto polypropylene (PP). PP was modified both at bulk and on the surface with poly(2MBA) by means of an oxidative pre-irradiation method ((60)Co source), in order to obtain a grafted polymer in which salicylic acid units were linked by means of labile ester bonds. The grafting percent depended on absorbed dose, reaction time, temperature and monomer concentration. The functionalized films were analyzed regarding structure (FTIR-ATR, SEM-EDX, fluorescence microscopy), temperature stability (TGA), interaction with aqueous medium (water contact angle and swelling), pH-responsive release and cytocompatibility (fibroblasts). In the obtained poly(2MBA)-grafted biomaterial, poly(2MBA) behaved as a polymeric prodrug that regulates salicylic acid release once in contact with aqueous medium, showing pH-dependent release rate.
Assuntos
Polímeros/química , Polipropilenos/química , Pró-Fármacos/química , Ácido Salicílico/química , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Liberação Controlada de Fármacos , Polímeros/administração & dosagem , Polímeros/farmacocinética , Polipropilenos/farmacocinética , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacocinética , Ácido Salicílico/farmacocinéticaRESUMO
The purpose of the current investigation was to explore the potential of polypropylene imine (PPI) dendrimers to deliver dithranol (DIT) topically and to evaluate its encapsulation, permeation and skin irritation potential. PPI (5.0 generation, 5.0 G) dendrimers and DIT-loaded PPI (DIT-PPI) were prepared and characterized by spectroscopy and transmission electron microscopy. DIT encapsulation, in vitro skin permeation study, skin irritation studies, fluorescent studies and tape stripping studies were performed. Loading of DIT was found to be pH dependent with maximum encapsulation at acidic pH (1.0 ± 0.02, 17.2 ± 0.56 and 57.1 ± 1.32% at 7.4, 5.5 and 1.2 pH, respectively). DIT-PPI showed significantly enhanced permeation rate constant and lesser skin irritation (11.61 ± 1.80 µg/cm(2)/h and 1.0, respectively) when compared with the plain DIT solution (2.72 ± 0.31 µg/cm(2)/h and 2.3, respectively). Skin separation studies and confocal laser scanning microscope images showed that the dye-loaded dendrimers exhibits deposition of dye in pilosebaceous compartment. These studies demonstrate that PPI can be exploited to improve the topical bioavailability of the molecules in a controlled pattern. The enhanced accumulation of DIT via dendrimer carrier within the skin might help optimize targeting of this drug to the epidermal and dermal sites, thus creating new opportunities for well-controlled, modern topical application of DIT for the treatment of psoriasis.
Assuntos
Antralina/administração & dosagem , Dendrímeros/administração & dosagem , Portadores de Fármacos/administração & dosagem , Nanopartículas/administração & dosagem , Polipropilenos/administração & dosagem , Absorção Cutânea/efeitos dos fármacos , Administração Cutânea , Animais , Antralina/química , Antralina/farmacocinética , Disponibilidade Biológica , Dendrímeros/química , Dendrímeros/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Concentração de Íons de Hidrogênio , Nanopartículas/química , Polipropilenos/química , Polipropilenos/farmacocinética , Psoríase/tratamento farmacológico , Psoríase/metabolismo , Ratos , Pele/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
The diagnosis and treatment of malignant melanoma by means of the formulation of active principles with dendrimeric nanoparticles is an area of great current interest. The identification and understanding of molecular mechanisms which ensure the integration of particular dendrimeric nanostructures in tumor cellular environment can provide valuable guidance in their coupling strategies with antitumor or diagnostic agents. Two structurally distinct maltose-shell modified 5th generation (G5) poly(propylene imine) (PPI) glycodendrimers fluorescently labeled, (a) with open maltose shell, cationic charged G5-PPI-OS and (b) with dense maltose shell and nearly neutral G5-PPI-DS, were tested in relation with several melanoma cell lines. We found that three melanoma cell lines internalize G5-PPI-DS structure more efficiently than non tumoral HEK297T cells. Furthermore, the internalization pathways of G5-PPI-OS and G5-PPI-DS are characteristic for each tumor cell phenotype and include more than one mechanism. As a general trend, large amounts of both G5-PPI-OS and G5-PPI-DS are internalized on cholesterol-dependent pathway in MJS primary melanoma cells and on non conventional pathways in SK28 metastatic melanoma cells. G5-PPI-OS, temporarily retained at plasma membrane in both cell lines, is internalized slower in metastatic than in primary phenotype. Unlike G5-PPI-OS, G5-PPI-DS is immediately endocytosed in both cell lines. The unconventional internalization pathway and trafficking, exclusively used by G5-PPI-DS in metastatic cells, is described at molecular level. The decay kinetics of fluorescent labeled G5-PPI-OS and G5-PPI-DS is distinct in the two cellular phenotypes. Both cationic and neutral maltose G5-PPI glycodendrimeric structures represent molecules based on which designing of new formulations for therapy or/and diagnosis of melanoma can be further developed.
Assuntos
Dendrímeros/farmacocinética , Maltose/farmacocinética , Melanoma/metabolismo , Polipropilenos/farmacocinética , Animais , Linhagem Celular Tumoral , Células Cultivadas , Dendrímeros/química , Humanos , Maltose/química , Camundongos , Polipropilenos/químicaRESUMO
Polypropylenimine (PPI) dendrimers have been widely used as effective delivery vehicles for drugs and nucleic acids during the past decade. However, biomedical applications of PPI dendrimers were limited because of their serious cytotoxicity and low drug loading capacity. In the present study, acetylated PPI dendrimers with different degrees of acetylation ranging from 14.2% to 94.3% were synthesized and used to encapsulate drugs, including methotrexate sodium, sodium deoxycholate and doxorubicin. Acetylated PPI dendrimers with a degree of acetylation >80% showed a significantly decreased cytotoxicity (>90% cell viability) on MCF-7 and A549 cells. The drug loading capacity of acetylated PPI dendrimers increased proportionally with the degree of acetylation on the dendrimer surface. In addition, 94.3% acetylated PPI dendrimers exhibited a pH-responsive release profile of anticancer drugs loaded within the nanoparticles. The cytotoxicities of methotrexate sodium and doxorubicin on MCF-7 and A549 cells were significantly reduced when they were complexed with acetylated PPI dendrimers with high degrees of acetylation (>80%), owing to sustained drug release from the dendrimers. The results suggest that surface acetylation can reduce the cytotoxicity and improve the anticancer drug loading capacity of cationic dendrimers, and that acetylated PPI dendrimers are promising vehicles for anticancer drugs in clinical trials.
Assuntos
Antineoplásicos/farmacologia , Citotoxinas/farmacologia , Dendrímeros/farmacologia , Sistemas de Liberação de Medicamentos , Nanopartículas , Polipropilenos/farmacologia , Acetilação , Antineoplásicos/química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citotoxinas/química , Citotoxinas/farmacocinética , Dendrímeros/química , Dendrímeros/farmacocinética , Humanos , Concentração de Íons de Hidrogênio , Polipropilenos/química , Polipropilenos/farmacocinéticaRESUMO
The persistence of marine debris such as discarded polymer bags has become globally an increasing hazard to marine life. To date, over 177 marine species have been recorded to ingest man-made polymers that cause life-threatening complications such as gut impaction and perforation. This study set out to test the decay characteristics of three common types of shopping bag polymers in sea turtle gastrointestinal fluids (GIF): standard and degradable plastic, and biodegradable. Fluids were obtained from the stomachs, small intestines and large intestines of a freshly dead Green turtle (Chelonia mydas) and a Loggerhead turtle (Caretta caretta). Controls were carried out with salt and freshwater. The degradation rate was measured over 49 days, based on mass loss. Degradation rates of the standard and the degradable plastic bags after 49 days across all treatments and controls were negligible. The biodegradable bags showed mass losses between 3 and 9%. This was a much slower rate than reported by the manufacturers in an industrial composting situation (100% in 49 days). The GIF of the herbivorous Green turtle showed an increased capacity to break down the biodegradable polymer relative to the carnivorous Loggerhead, but at a much lower rate than digestion of natural vegetative matter. While the breakdown rate of biodegradable polymers in the intestinal fluids of sea turtles is greater than standard and degradable plastics, it is proposed that this is not rapid enough to prevent morbidity. Further study is recommended to investigate the speed at which biodegradable polymers decompose outside of industrial composting situations, and their durability in marine and freshwater systems.
Assuntos
Líquidos Corporais/química , Trato Gastrointestinal/química , Plásticos/farmacocinética , Polímeros/farmacocinética , Tartarugas/metabolismo , Poluentes Químicos da Água/farmacocinética , Animais , Biodegradação Ambiental , Feminino , Plásticos/análise , Polietileno/análise , Polietileno/farmacocinética , Polímeros/análise , Polipropilenos/análise , Polipropilenos/farmacocinética , Poluentes Químicos da Água/análiseRESUMO
The goal of this study was to evaluate the effect of dentin treatment duration (10 minutes, 24 hours, and seven days) with Tetraclean on its residual antibacterial activity in bovine root dentin. Results showed that the number of colony-forming units in all three experimental groups was zero at the first culture. Furthermore, the 10-minute group and seven-day group demonstrated the highest and the lowest number of colony-forming units, respectively.
Assuntos
Anti-Infecciosos Locais/farmacocinética , Compostos de Cetrimônio/farmacocinética , Ácido Cítrico/farmacocinética , Cavidade Pulpar/metabolismo , Dentina/metabolismo , Doxiciclina/farmacocinética , Polipropilenos/farmacocinética , Irrigantes do Canal Radicular/farmacocinética , Animais , Anti-Infecciosos Locais/química , Anti-Infecciosos Locais/farmacologia , Bovinos , Compostos de Cetrimônio/química , Compostos de Cetrimônio/farmacologia , Ácido Cítrico/química , Ácido Cítrico/farmacologia , Contagem de Colônia Microbiana , Cavidade Pulpar/efeitos dos fármacos , Cavidade Pulpar/microbiologia , Dentina/efeitos dos fármacos , Dentina/microbiologia , Doxiciclina/química , Doxiciclina/farmacologia , Incisivo , Estudos Longitudinais , Polipropilenos/química , Polipropilenos/farmacologia , Irrigantes do Canal Radicular/química , Tensão Superficial , Fatores de Tempo , Raiz Dentária/efeitos dos fármacos , Raiz Dentária/metabolismo , Raiz Dentária/microbiologia , MolhabilidadeRESUMO
We here present an evaluation of the carrier performance of nanoparticles that are biofunctional, i.e. derivatized to provide a controlled biological activity, and environmentally responsive, since they respond to the presence of oxidants. In particular, we focus on the possibilities (a) to make the nanoparticles detectable and (b) to control their uptake in phagocytic cells, which determines their lifetime in vivo. We first describe techniques for labeling selectively the nanoparticle surface or bulk with imaging moieties (fluorophores or gold). We then show how surface composition and size, which are both controlled through the use of PEG derivatives, influence uptake by macrophages in vitro and blood circulation in vivo: for example, in vitro uptake is negligible for small (40 nm) particles but not for larger (100 nm) ones and, correspondingly, in vivo blood circulation half-life time decreases from 6.0 to 2.9 h. However, upon decoration with RGD peptides also the small particles can be significantly internalized.
Assuntos
Monócitos/metabolismo , Nanopartículas/química , Polipropilenos/química , Polipropilenos/farmacocinética , Sulfetos/química , Sulfetos/farmacocinética , Animais , Portadores de Fármacos , Teste de Materiais , Camundongos , Tamanho da Partícula , Ratos , Ratos Sprague-DawleyAssuntos
DNA Catalítico/administração & dosagem , Dendrímeros/administração & dosagem , Oligonucleotídeos/administração & dosagem , Polipropilenos/administração & dosagem , Transfecção/métodos , Linhagem Celular Tumoral , DNA/administração & dosagem , DNA/química , DNA/farmacocinética , DNA Catalítico/química , DNA Catalítico/farmacocinética , Dendrímeros/síntese química , Dendrímeros/química , Dendrímeros/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Feminino , Genes myc , Humanos , Oligonucleotídeos/química , Oligonucleotídeos/farmacocinética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/terapia , Polipropilenos/síntese química , Polipropilenos/química , Polipropilenos/farmacocinéticaRESUMO
The systemic delivery of genetic therapies required for the treatment of inaccessible tumors and metastases remains a challenge despite the development of various viral and synthetic vector systems. Here we show that a synthetic vector system based on polypropylenimine dendrimers has the desired properties of a systemic delivery vehicle and mediates efficient transgene expression in tumors after i.v. administration. The systemic tumor necrosis factor alpha (TNFalpha) gene therapy was efficacious in the experimental treatment of established A431 epidermoid carcinoma, C33a cervix carcinoma, and LS174T colorectal adenocarcinoma. Specifically, the systemic injection of dendrimer nanoparticles containing a TNFalpha expression plasmid regulated by telomerase gene promoters (hTR and hTERT) leads to transgene expression, regression of remote xenograft murine tumors, and long-term survival of up to 100% of the animals. Interestingly, these dendrimers and, to a lesser extent, other common polymeric transfection agents also exhibit plasmid-independent antitumor activity, ranging from pronounced growth retardation to complete tumor regression. The genetic therapy as well as treatment with dendrimer alone was well tolerated with no apparent signs of toxicity in the animals. The combination of intrinsic dendrimer activity and transcriptionally targeted TNFalpha when complexed was significantly more potent than either treatment alone or when both were administered in sequence. The combination of pharmacologically active synthetic transfection agent and transcriptionally targeted antitumor gene creates an efficacious gene medicine for the systemic treatment of experimental solid tumors.
Assuntos
Terapia Genética/métodos , Vetores Genéticos/farmacologia , Neoplasias/terapia , Polipropilenos/farmacologia , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/terapia , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/terapia , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/terapia , Feminino , Vetores Genéticos/química , Vetores Genéticos/genética , Vetores Genéticos/farmacocinética , Humanos , Óperon Lac , Nanoestruturas/química , Neoplasias/genética , Neoplasias/metabolismo , Plasmídeos/genética , Polipropilenos/química , Polipropilenos/farmacocinética , Regiões Promotoras Genéticas , Transfecção/métodos , Fator de Necrose Tumoral alfa/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/terapia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A novel dendrimeric compound is designed with the objective of simultaneously addressing issues commonly encountered in drug delivery, i.e., stability in biological milieu as well as targeting. For this purpose, a multifunctional dendrimeric system derived from diaminobutane poly(propylene imine) dendrimers (DAB) is prepared bearing at its external surface poly(ethylene glycol) chains and guanidinium moieties. For these moieties, it has been established that they exhibit protective and targeting properties, respectively. The release of encapsulated compounds is triggered by titration with acids followed by the addition of sodium chloride solution. Specifically for pyrene, the solubilization site of which can be clearly traced, protonation leads to a distribution between the core and the poly(ethylene glycol) chains in the periphery of the dendrimer while it is released to the aqueous bulk solution by the addition of sodium chloride. The release of betamethasone valerate is also triggered by the addition of sodium chloride solution.
Assuntos
Betametasona/análogos & derivados , Sistemas de Liberação de Medicamentos/métodos , Polipropilenos/química , Polipropilenos/farmacocinética , Ácidos , Betametasona/química , Betametasona/farmacocinética , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Espectroscopia de Ressonância Magnética , Polietilenoglicóis/química , Sais , SolubilidadeRESUMO
The present work focused on the design of an assembled drug delivery system (DDS) to provide multifunctions, such as drug protection, self-regulated oscillatory release, and targeted uni-directional delivery by a bilayered self-folding gate and simple surface mucoadhesion. In this device, a pH-sensitive hydrogel together with a poly(hydroxyethyl methacrylate) (HEMA) barrier was used as a gate to control drug release. In addition, poly(HEMA) coated with poly(ethylene oxide)/poly(propylene oxide)/poly(ethylene oxide) (PEO-PPO-PEO) surfactant was utilized to enhance mucoadhesion on the device surface. The release profiles of two model drugs, acid orange 8 (AO8) and bovine serum albumin (BSA) were studied in this assembled system, which compared with the conventional drug-entrapped carriers and enteric-coating systems. Furthermore, targeted uni-directional release was demonstrated in a side-by-side diffusion cell. In conclusion, for such an assembled device, the poly(HEMA) layer not only affects the folding direction but also serves as a barrier to protect the model drugs. The release time can be controlled by the thickness of the bilayered gate and the drug reservoir. Due to the reversible swelling behavior of poly(methyacrylic acid-g-ethylene glycol) (p(MAA-g-EG)) gels, the bilayered gate can sense the environmental pH change and achieve an oscillatory release pattern. Moreover, the local targeting and uni-directional release have been successfully demonstrated in vitro.
Assuntos
Preparações de Ação Retardada/farmacocinética , Hidrogel de Polietilenoglicol-Dimetacrilato/farmacocinética , Corantes/química , Corantes/farmacocinética , Preparações de Ação Retardada/química , Difusão/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Compostos de Epóxi/química , Compostos de Epóxi/farmacocinética , Hidrogel de Polietilenoglicol-Dimetacrilato/química , Concentração de Íons de Hidrogênio , Metacrilatos/química , Metacrilatos/farmacocinética , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Polímeros/química , Polipropilenos/química , Polipropilenos/farmacocinética , Soroalbumina Bovina/química , Soroalbumina Bovina/farmacocinética , Tensoativos/química , Tensoativos/farmacocinética , Fatores de Tempo , Molhabilidade/efeitos dos fármacosRESUMO
Regeneration of skeletal tissues has been recognized as a new means for reconstruction of skeletal defects. We investigated the feasibility of an injectable and expandable porous implant system for in situ regeneration of bone. Therefore, a composite biodegradable foaming cement based on poly(propylene fumarate) was injected into a critical size defect made in the rat tibia. Animals were divided into two groups comparing the foam in the experimental group against sham-operated animals having a drill hole but no implant in the control group. Eight animals were included in each group. Animals were sacrificed at 1, 3, and 7 weeks postoperatively. Implantation sites were then evaluated with histologic and histomorphometric methods. Results of this study showed that defects did not heal in sham-operated animals. In the experimental group, metaphyseal and cortical defects healed within the first postoperative week by formation of immature woven bone. At the site of the cortical drill hole defect, healing was noted to progress to complete closure by formation of mature bone. Histomorphometry corroborated these findings and showed that metaphyseal bone remodeling peaked at 1 week postoperatively and then decreased as healing of the cortical defect progressed. This suggests that near-complete restoration of the original state of the tibial bone occurred in this animal model supporting the concept of in situ bone regeneration by application of engineered biodegradable porous scaffolds. () ()
Assuntos
Cimentos Ósseos , Fumaratos , Polipropilenos , Tíbia/lesões , Cicatrização , Animais , Biodegradação Ambiental , Cimentos Ósseos/farmacocinética , Fumaratos/química , Fumaratos/farmacocinética , Masculino , Microscopia Eletrônica de Varredura , Polipropilenos/química , Polipropilenos/farmacocinética , Ratos , Ratos Sprague-Dawley , Tíbia/cirurgiaRESUMO
Previous studies have shown the effectiveness of partially resorbable arterial prostheses in the rabbit. This study compares these same compound prostheses with commercial graft materials in the dog. Conduits 4 mm inner diameter X 50 mm in length were woven from composite yarns containing 69% polyglactin 910 (PG910)/31% polypropylene or containing 70% polydioxanone/30% polypropylene. Nonresorbable controls were woven Dacron and expanded polytetrafluoroethylene (ePTFE). Baseline platelet aggregometry to 10(-5) mol/L adenosine diphosphate was performed. Seventy prostheses were implanted into the aorto-ilac positions, and the prosthesis/tissue complexes were harvested serially from 2 weeks to 1 year. Explanted specimens were photographed and fixed for light microscopy and for scanning and transmission electron microscopy. Results showed no aneurysms or perigraft hematomas. Overall patency for the PG910/polypropylene grafts was 18 of 20 (90%) and for polydioxanone/polypropylene was 19 of 22 (86%). For Dacron and ePTFE, 13 of 19 (68%) and 6 of 11 (54%) remained patent at time of explantation. The partially resorbable grafts, as a group, had significantly greater patency than the control grafts (p less than 0.03). Platelet aggregometry was not predictive of graft patency. Histologic analysis of the partially bioresorbable groups showed inner capsules (IC) composed of myofibroblasts and collagen beneath confluent endothelialized surfaces by 1 month. Kinetics of IC formation paralleled the rates of resorption of the resorbable components. IC cellularity and thickness were greater than those within Dacron or ePTFE. This study suggests an enhanced transinterstitial endothelial cell and myofibroblast ingrowth into the ICs of partially resorbable grafts and shows the effectiveness of these prostheses in the dog.
Assuntos
Prótese Vascular , Absorção , Animais , Vasos Sanguíneos/patologia , Vasos Sanguíneos/ultraestrutura , Cães , Polidioxanona/farmacocinética , Polietilenotereftalatos , Poliglactina 910/farmacocinética , Polipropilenos/farmacocinética , Politetrafluoretileno , Complicações Pós-Operatórias , Período Pós-Operatório , Fatores de Tempo , Grau de Desobstrução VascularRESUMO
Migration rates of radiolabelled antioxidants, Irganox-1010 (I-1010) and Irganox-1076 (I-1076), were measured from low- and high-density polyethylenes (LDPE, HDPE) and polypropylene (PP) at temperatures up to 135 degrees C. Water, 8 and 95 per cent aqueous ethanol and corn oil were employed as food simulating liquids (FSL). The experiments were conducted in a high-pressure cell in a manner that allowed contact between the polyolefin plaque and the FSL only during the test period and not while being heated. The migrations of the antioxidants varied with the square root of time, and the Fickian diffusion coefficients could be correlated with temperature in an Arrhenius fashion. Under comparable test conditions, antioxidant migrations were largest from PP for aqueous simulants, but for non-aqueous simulants the highest losses were from LDPE. In both instances lowest losses were from HDPE. In most instances there was little difference between the migration behaviour of I-1010 and I-1076. A few tests were conducted to measure the antioxidant migrations to foods. The losses were usually larger than those to water but below those to corn oil.